Laser photomedicine is a well-established therapeutic modality for a wide variety of conditions. To date, the use of ophthalmic lasers has been limited to either short (around one microsecond or shorter) pulse systems for sub-cellular targeting, or long (hundreds of microseconds and longer) pulse systems that indiscriminately denature relatively large volumes of tissue.
For example, present standard retinal photocoagulative treatment for conditions such as Diabetic Retinopathy, and Age-Related Macular Degeneration utilize visible laser light with exposure durations on the order of 100 ms. Generation of heat due to absorption of visible laser light occurs predominantly in the retinal pigmented epithelium (RPE) and pigmented choriocappilaris, the melanin containing layers directly beneath the photoreceptors of the sensory retina. FIG. 1 schematically illustrates the ocular structure around the melanin layer, which includes the RPE disposed between the sensory retina and the choroid. Due to heat diffusion during long exposures, this standard therapy also irreversibly damages the overlying sensory retina.
Although it does halt the progress of the underlying disease, such irreversible damage decreases the patient's vision by destroying not only the photoreceptors in the irradiated portion of the retina but also by creating permanent micro-scotomas, and possibly also damaging the retinal nerve fibers that traverse the targeted portion of the retina. Such nerve fiber damage eliminates the signals it would have carried from distal areas of the retina, thus unnecessarily further worsening the patient's vision.
The RPE may be thought of as a 10 μm thick monocellular structure containing a 4 μm thick layer of pigment. The characteristic thermal relaxation time (τr) may be approximated by the relation:τr=d2/4α  (1)where d is the thickness of the layer and α is the tissue's thermal diffusivity (in this case that of water; 0.14 mm2s−1), as discussed in H S Carlslaw, J C Jaeger, “Conduction of Heat in Solids” Second Edition, Oxford University Press, 1959. This shows that the entire RPE layer itself and the pigmented zone within it would have characteristic thermal relaxation times of approximately 180 μs and 30 μs, respectively. During a typical photocoagulative pulse of 100 ms, heat generated in the RPE and in pigmented choroid will diffuse to the distance of about 220 μm, thus leading to irreversible damage to the inner retina.
To ameliorate the abovementioned collateral damage unavoidably suffered by the use of “long” pulses, the use of a burst of microsecond or sub-microsecond pulses has been recently investigated. This approach yields purely photomechanical damage that can be confined to the pigmented organelles of the RPE (melanosomes). It is believed that such confined sub-cellular damage can instigate a wound healing response, which subsequently rebuilds the RPE without causing damage to the photoreceptors. Although it would be simpler to deliver such short pulses of sufficient energy to unequivocally damage the RPE cells themselves, rather than just the melanosomes, the energy required to do so at such short pulses very often ruptures Bruch's membrane, which is immediately behind the RPE. This ultimately worsens the condition. Such a technique has been described by Latina in U.S. Pat. No. 5,549,596, where the use of pulses that are of sufficiently short duration such that the heat produced by their absorption is confined to the absorbing (pigmented) cell alone is discussed. This approach is risky, however, as it endangers the integrity of the target and adjacent structures due to the photomechanical forces imparted. The relatively narrow therapeutic window in this approach, and lack of a visible endpoint of the treatment necessitate the use of specialized diagnostic devices to discern the appropriate retinal irradiance for each patient. Furthermore, difficulty in generating these short pulses, require relatively complicated, expensive, and delicate equipment, as compared to that of the systems for generating 100 ms pulse treatment.
The use of a pulse-train of near-infrared light from a semiconductor laser source has also been investigated in an attempt to limit the extent of photocoagulative damage to the outer retina. This approach makes use of the fact that biochemical damage is additive when created over time, and such time is relatively short when compared the body's response to that damage, such as is described in U.S. Pat. No. 5,302,259 by Birngruber. To date, the clinical results of such systems have been lackluster, even when used in conjunction with an exogenous dye to increase the absorption of the infrared light. Pulse trains of 810 nm light of a 200 ms overall duration and 10% duty cycle (typically 100 individual 200 μs pulses, uniformly spaced 1800 μs apart) have been used to damage the RPE. Due to heat accumulation during the train and non-specific absorption of the near infrared light, such treatment ultimately caused indiscriminate damage to large volumes of tissue because it simply acted as long pulse rather than an ensemble of “short” individual pulses.
Theoretical modeling by the inventors of the heating effects produced by 100, 500, and 1000 μs pulses directly in the RPE and tissue 5 μm away (the interface between the RPE and the outer sensory retina) is shown in FIG. 3. This type of thermal injury is well described by an Arrhenius molecular damage model. As is known in the art for such cases, the amount of molecular damage is only linearly dependent on the length of time a temperature is held, but exponentially dependent upon the ultimate temperature reached. With that in mind, one may consider that the differences in the peak temperatures achieved are an indicator of the spatial selectivity of these pulses.
Likewise, in photomedical treatments to alleviate the increased intraocular pressure associated with glaucoma either disproportionately long or short pulses are currently used. To date, similar to retinal treatments, the use of pulses on the order of 100 ms, 1 μs and 5 ns have been reported with varying degrees of overall clinical success. Here the target chromophore is pigment accumulated in the trabecular meshwork of the eye's anterior chamber, as shown schematically in FIG. 4. The sizes of the targeted structures in the trabecular meshwork are similar to those described above, thus the same pulse duration ranges are relevant there as well.
Accordingly, there is a need for a flexible, robust, cost-effective way to provide predictable and minimally traumatic ophthalmic photomedical treatment such as, but not limited to, the retina and trabecular meshwork that is not provided by known methods or devices.